EP2305232A1 - Mélange synergétique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires - Google Patents

Mélange synergétique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires Download PDF

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EP2305232A1
EP2305232A1 EP20100179109 EP10179109A EP2305232A1 EP 2305232 A1 EP2305232 A1 EP 2305232A1 EP 20100179109 EP20100179109 EP 20100179109 EP 10179109 A EP10179109 A EP 10179109A EP 2305232 A1 EP2305232 A1 EP 2305232A1
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hypertension
pharmaceutically acceptable
acceptable salt
group
renal failure
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EP2305232B1 (fr
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William Hewitt
Daniel Lucius Vasella
Randy Lee Webb
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Noden Pharma DAC
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P27/02—Ophthalmic agents
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    • A—HUMAN NECESSITIES
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    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
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    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention especially relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and at least one therapeutic agent selected from the group consisting of
  • At least one therapeutic agent shall mean that in addition to the compound of formula (I) one or more, for example two, furthermore three, active ingredients as specified according to the present invention can be combined.
  • Renin inhibit the action of the natural enzyme renin.
  • the latter passes from the kidneys into the blood where it effects the cleavage of angiotensinogen releasing the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to form the octapeptide angiotensinogen II.
  • the octapeptide increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating from the adrenal glands the sodium-ionretaining hormone aldosterone, accompanied by an increase in extracellular fluid volume. That increase can be attributed to the action of angiotensin II.
  • Inhibitors of the enzymatic activity of renin bring about a reduction in the formation of angiotensin I. As a result a smaller amount of angiotensin II is produced.
  • the reduced concentration of that active peptide hormone is the direct cause of e.g. the hypotensive effect of renin inhibitors.
  • the renin inhibitor of formula (I), chemically defined as 2(S),4(S),5(S),7(S)-N-(3-amino-2,2-dimethy)-3-oxopropyl)-2.7-di(1-methylethyl)-4-hydroxy-5 - amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide, is specifically disclosed in EP 678503 A .
  • the hemi-fumarate salt thereof is particularly preferred.
  • AT 1 -receptor antagonists also called angiotensin II receptor antagonists
  • angiotensin II receptor antagonists are understood to be those active ingredients that bind to the AT 1 -receptor subtype of angiotensin II receptor but do not result in activation of the receptor.
  • these antagonists can, for example, be employed as antihypertensives or for treating congestive heart failure.
  • the class of AT 1 receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones.
  • Preferred AT 1 -receptor antagonist are those agents that have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
  • HMG-Co-A reductase inhibitors also called ⁇ -hydroxy- ⁇ -methylglutaryl-co-enzyme-A reductase inhibitors
  • HMG-Co-A reductase inhibitors are understood to be those active agents that may be used to lower the lipid levels including cholesterol in blood.
  • the class of HMG-Co-A reductase inhibitors comprises compounds having differing structural features.
  • the compounds that are selected from the group consisting of atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or, in each case, a pharmaceutically acceptable salt thereof.
  • HMG-Co-A reductase inhibitors are those agents which have been marketed, most preferred is fluvastatin and pitavastatin and also atorvastatin or, in each case, a pharmaceutically acceptable salt thereof.
  • ACE-inhibitors also called angiotensin converting enzyme inhibitors
  • the class of ACE inhibitors comprises compounds having differing structural features.
  • Preferred ACE inhibitors are those agents that have been marketed, most preferred are benazepril and enalapril.
  • the class of CCBs essentially comprises dihydropyridines (DHPs) and non-DHPs such as diltiazem-type and verapamil-type CCBs.
  • DHPs dihydropyridines
  • non-DHPs such as diltiazem-type and verapamil-type CCBs.
  • a CCB useful in said combination is preferably a DHP representative selected from the group consisting of amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline.
  • CCBs are therapeutically used, e.g. as anti-hypertensive, anti-angina pectoris or anti-arrhythmic drugs.
  • Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, e.g. dependent on the specific CCB, a pharmaceutically acceptable salt thereof.
  • DHP is amlodipine or a pharmaceutically acceptable salt, especially the besylate, thereof.
  • An especially preferred representative of non-DHPs is verapamil or a pharmaceutically acceptable salt, especially the hydrochloride, thereof.
  • Aldosterone synthase inhibitor is an enzyme that converts corticosterone to aldosterone by hydroxylating cortocosterone to form 18-OH-corticosterone and 18-OH-corticosterone to aldosterone.
  • the class of aldosterone synthase inhibitors is known to be applied for the treatment of hypertension and primary aldosteronism comprises both steroidal and non-steroidal aldosterone synthase inhibitors, the later being most preferred.
  • the class of aldosterone synthase inhibitors comprises compounds having differing structural features.
  • non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole ( US patents 4617307 and 4889861 ) of formula
  • a preferred steroidal aldosterone antagonist is eplerenone (cf. EP 122232 A ) of the formula or spironolactone.
  • a preferred dual angiotensin converting enzyme/neutral endopetidase (ACE/NEP) inhibitor is, for example, omapatrilate (cf. EP 629627 ), fasidotril or fasidotrilate, or Z 13752A (cf. WO 97/24342 ) or, if appropriable, a pharmaceutically acceptable salt thereof.
  • Endothelin is a highly potent vasoconstrictor peptided synthesized and released by the vascular endotleium. Endothelin exists in three isoforms (ET-1, ET-2 and ET-3). (ET shall meand any or all othe isoforms of ET). Elevated levels of ET have been reported in plasma a fomr patients with e.g. essential hypertension. Endothelin receptor antagonist can be used to inhibit the vasoconstrictive effects induced by ET.
  • a preferred endothelin antagonist is, for example, bosentan (cf. EP 526708 A ), enrasentan (cf. WO 94/25013 ), atrasentan (cf. WO 96/06095 ), especially atrasentan hydrochloride, darusentan (cf. EP 785926 A ), BMS 193884 (cf. EP 702012 A ), sitaxentan (cf. US 5594021 ), especially sitaxsentan sodium, YM 598 (cf. EP 882719 A ), S 0139 (cf. WO 97/27314 ), J 104132 (cf. EP 714897 A or WO 97/37665 ), furthermore, tezosentan (cf. WO 96/19459 ), or in each case, a pharmaceutically acceptable salt thereof.
  • bosentan cf. EP 526708 A
  • enrasentan cf. WO 94/25013
  • a diuretic is, for example, a thiazide derivative selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlarothalidon. The most preferred is hydrochlorothiazide.
  • an active agent selected from the group consisting of valsartan, fluvastatin, atorvastatin, pitavastatin, benzepril, enalapril, amlodipine, especially the besylate thereof, the (+) enantiomer of fadrozole, eplerenone, omapatrilate
  • combinations such as a combined preparations or pharmaceutical compositions, respectively, comprising the renin inhibitor of formula (I) or a pharmaceutically accepted salt thereof and one active agent selected from the group consisting of valsartan, fluvastatin, atorvastatin, pitavastatin, benzepril, enalapril, amlodipine, especially the besylate thereof, the (+) enantiomer of fadrozole, eplerenone, omapatrilate, Z 13752A, sitaxsentan, especially sitaxsentan sodium, and darusentan, furthermore comprising as third active agent hydrochlorothiazide.
  • one active agent selected from the group consisting of valsartan, fluvastatin, atorvastatin, pitavastatin, benzepril, enalapril, amlodipine, especially the besylate thereof, the (+) enantiomer of fadrozole, eplerenone, omapa
  • the structure of the active agents identified by generic or tradenames may be taken from the actual edition of the standard compendium "The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
  • the corresponding active ingredients or a pharmaceutically acceptable salts thereof may also be used in form of a solvate, such as a hydrate or including other solvents, used for crystallization.
  • the compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
  • the compounds having an acid group for example COOH can also form salts with bases.
  • both active ingredients are administered as a fixed combination, i.e. as a single tablet, in all cases desribed herein. Taking a single tablet is even easier to handle than taking two tablets at the same time. Furthermore, the packaging can be accomplished with less effort.
  • the combination according to the present invention comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by various routes of administration but are tested in this example using a continuous infusion via subcutaneously-implanted osmotic minipumps.
  • Each agent can be tested over a wide-range of dosages to determine the optimal drug level for each agent in combination to elicit the maximal response.
  • treatment groups consisting of at least 6 animals per group. Each study is best performed in which the effects of the combination treatment group are determined at the same time as the individual components are evaluated.
  • drug effects may be observed with acute administration (such as 1 day), it is preferable to observe responses in a chronic setting as shown below in which experiments were done over a two to three week observation period.
  • the long-term study is of sufficient duration to allow for the full development of compensatory responses to occur and therefore, the observed effect will most likely depict the actual responses of the test system representing sustained or persistent effects.
  • the effects on blood pressure depicted below represent a synergistic antihypertensive effect when the two agents are used in combination.
  • the combination therapy can be compared to that of the monotherapy groups by determining the maximum change in blood pressure or the area under the curve (AUC) for change in blood pressure over time in each of the treatment groups. All values are represented as the group mean ⁇ SEM. Statistical significance is obtained when p ⁇ 0.05.
  • the AUC values for each of the treatment groups can be compared statistically using a one-way ANOVA followed by the appropriate post-hoc analysis, for example by performing a Tukey's test.
  • Blood pressure can be reduced to a similar degree using lower dosages of each of the components when given in combination than when the individual monotherapies are administered.
  • An additional unexpected finding is that the blood pressure can be lowered to a greater extent with the combination than when the individual compound of formulat (I) or a pharmaceutically acceptable salt thereof is given alone at a higher dosage.
  • the valuable potential of the combination of the present invention for the prevention and treatment of myocardial infarction can be found using the following test model.
  • CAO coronary artery occlusion
  • Infarct size Six ⁇ m-thick transverse histological sections of the left ventricle are stained with nitroblue tetrazolium and acquired by a B/W XC-77CE CCD video camera (Sony). The resulting image is processed on a KS 300 image analysis system (Carl Zeiss Vision) using a software specifically developed (Porzio et al., 1995). A single operator blinded to treatment interactively defines the boundaries of the interventricular septum, and the infarcted area on each section is semiautomatically identified as the area of unstained ventricular tissue. The software automatically calculates for each component of the ventricular section defined as the chamber, septum, infarcted area, infarcted LV wall and viable LV wall, a set of geometric parameters (Porzio et a / ., 1995).
  • Hearts are fixed in situ, by retrograde perfusion with buffered 4% formaldehyde after arrest in diastole by i.v. injection of 0.5 M KCI. After fixation, the left ventricle (LV) and the free wall of the right ventricle are separately weighed; LV longer diameter is measured with a caliper.
  • LV histological sections are stained with hematoxylin & eosin for qualitative examination and to quantify cardiomyocytes cross-sectional area with a semi-automated image analysis routine. lnterstitial collagen deposition in LV is evaluated on Sirius red stained sections with a semi-automated image analysis routine (Masson et al., 1998).
  • Collagen content in LV spared myocardium LV tissue in the spared myocardium is homogenized, subjected to PAGE-SDS electrophoresis and electroblotted onto nitrocellulose membrane. The blots are exposed to primary antibodies, i.e. rabbit anti-rat collagen type I or type III antiserum (Chemicon). The primary antibodies are recognized by secondary antibodies conjugated to alkaline phosphatase (for colagen type I) or peroxidase (collagen type III).
  • LV chamber volume is determined in hearts arrested in diastole (KCI) and fixed in formalin under a hydrostatic pressure equivalent to the measured LV end-diastolic pressure.
  • a metric rod is inserted into the LV to measure LV inner length.
  • the transverse diameters of the LV chamber are measured in two 1-mm thick transverse sections near to the base and the apex of the ventricle (Jeremic et al ., 1996).
  • the chamber volume is computed from an equation integrating transverse diameters and inner length.
  • a microtip pressure transducer (Millar SPC-320) connected to a recorder (Windograf, Gould Electronics) is inserted into the right carotid artery to record systolic and diastolic blood pressures.
  • the pressure transducer is advanced into the LV to measure LV systolic (LVSP) and end-diastolic (LVEDP) pressures, the first derivative of LV pressure over time (+dP/dt) and heart rate.
  • LVSP LV systolic
  • LVEDP end-diastolic
  • Non-invasive blood pressure Systolic blood pressure and heart rate are measured by the tail-cuff method (Letica LE 5002) in conscious rats.
  • Urine electrolytes, hormones Rats are individually housed in metabolic cages and 24-h urine collected on 1 ml HCI 6N. Water intake is measured. Urine catecholamines are extracted on Bondelut C 18 columns (Varian), separated by HPLC (Apex-11 C18, 3 ⁇ m. 50x4.5 mm analytical column, Jones Chromatography) and quantified with an electrochemical detector (Coulochem II, ESA) (Goldstein et al ., 1981). Plasma and urine aldosterone, and plasma angiotensin II are determined with specific radioimmunoassays
  • Urine sodium and potassium are measured by flame photometry.
  • Endothelial dysfunction is being acknowledged as a critical factor in vascular diseases.
  • the endothelium plays a bimodal role as the source of various hormones or by-products with opposing effects: vasodilation and vasoconstriction, inhibition or promotion of growth, fibrinolysis or thrombogenesis, production of anti-oxidants or oxidising agents.
  • Genetically predisposed hypertensive animals with endothelial dysfunction constitute a valid model for assessing the efficacy of a cardiovascular therapy.
  • Endothelial disfunction is characterized by, for example, increased oxidative stress, causing decreased nitric oxide, increased factors involved in coagulation or fibrinolysis such as plasminogen activating inhibitor-1 (PAI-1), tissue factor (TF), tissue plasminogen activator (tPA), increased adhesion molecules such as ICAM and VCAM, increased growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
  • PAI-1 plasminogen activating inhibitor-1
  • TF tissue factor
  • tPA tissue plasminogen activator
  • ICAM interleukinogen activator
  • VCAM increased adhesion molecules
  • growth factors such as bFGF, TGFb, PDGF, VEGF, all factors causing cell growth inflammation and fibrosis.
  • the treatment e.g. of endothelial dysfunction can be demonstrated in the following pharmacological test:
  • the drugs are administered in drinking fluid.
  • the dose of enalapril is selected from the work of Sweet et al.
  • Body weight is measured every week.
  • Systolic blood pressure and heart rate are recorded by tail cuff plethysmography 3 and 2 weeks before starting the study and at 2 weeks after drug administration.
  • Urine is collected over a 24 hour period from rats kept in individual (metabolic) cages the week before starting treatment and at weeks 4 and 12 for volume measurement and protein, creatinine, sodium and potassium determination using standard laboratory methods.
  • blood samples are withdrawn from the retro-orbital plexus (maximum 1 ml) for creatinine, Na + and K + assays.
  • mice Ten rats from each group are sacrificed at 4 weeks for collection of kidney and heart for morphological analysis. The remaining rats are sacrificed at 12 weeks. Cardiac and kidney weight is recorded. Terminal blood sampling is performed in 5 % EDTA at 4 (morphometry study) and 12 (end of the study) weeks for aldosterone, determination by radioimmunoassay using a DPC coat-a-count aldosterone-RIA kit (Bühlmann, Switzerland).
  • both the compound of formula (I) in form of the hemi-fumarate and enalapril treatment lead to significant improvements in survival rates.
  • the surprising observation is that, in this model, blockade of the RAS with low doses of the renin inhibitor of formula (I) and, for example, and enalapril improved survival despite persistent kidney dysfunction and high blood pressure. There is no decrease in proteinuria and no reduction of kidney lesions. Kidney and heart sections show glomeruloslerosis, fibrinoid necrosis and fibrosis.
  • compositions of the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
  • composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
  • the invention furthermore relates to a method for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of
  • the present inveniton relates to the use of a combination of the renin inhibitor of formula (I) or a pharmaceutically acceptable salt thereof with at least one therapeutic agent selected from the group consisting of
  • the invention furthermore relates to a pharmaceutical composition for the prevention of, delay of progression of, treatment of a disease or condition selected from the group consisting of
  • compositions of the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.
  • the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, separately or in a fixed combination.
  • composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.
  • a further aspect of the present invention is a kit for the prevention of, delay of progression of, treatment of a disease or condition according to the present invention comprising
  • the present invention likewise relates to a "kit-of-parts", for example, in the sense that the components to be combined according to the present invention can be dosed independently or by use of different fixed combinations with distinguished amounts of the components, i.e. simultaneously or at different time points.
  • the parts of the kit of parts can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components.
  • the invention furthermore relates to a commercial package comprising the combination according to the present invention together with instructions for simultaneous, separate or sequential use.
  • These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances.
  • the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80%, of the active compound.
  • Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes.
  • compositions for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commerically available.
  • an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 75 kg in weight.
  • the dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.
  • the pharmaceutical preparation will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising an amount, being together with the further component(s) jointly effective, e.g.
  • the doses of renin inhibitor of formula (I) to be administered to warm-blooded animals, for example human beings, of, for example, approximately 70kg body weight, especially the doses effective in the inhibition of the enzyme renin, e.g. in lowering blood pressure and/or in improving the symptoms of glaucoma, are from approximately 3mg to approximately 3g, preferably from approximately 10mg to approximately 1 g, for example approximately from 20mg to 200mg, per person per day, divided preferably into 1 to 4 single doses which may, for example, be of the same size. Usually, children receive about half of the adult dose.
  • the dose necessary for each individual can be monitored, for example by measuring the serum concentration of the active ingredient, and adjusted to an optimum level.
  • Single doses comprise, for example, 10, 40 or 100 mg per adult patient.
  • Valsartan as a representative of the class of AT 1 -receptor antagonists, will be supplied in the form of suitable dosage unit form, for example, a capsule or tablet, and comprising a therapeutically effective amount, e.g. from about 20 to about 320 mg. of valsartan which may be applied to patients.
  • the application of the active ingredient may occur up to three times a day, starting e.g. with a daily dose of 20 mg or 40 mg of valsartan, increasing via 80 mg daily and further to 160 mg daily up to 320 mg daily.
  • valsartan is applied twice a day with a dose of 80 mg or 160 mg, respectively, each.
  • Corresponding doses may be taken, for example, in the morning, at mid-day or in the evening.
  • Preferred is b.i.d. administration.
  • preferred dosage unit forms of HMG-Co-A reductase inhibitors are, for example, tablets or capsules comprising e.g. from about 5 mg to about 120 mg, preferably, when using fluvastatin, for example, 20 mg, 40 mg or 80 mg (equivalent to the free acid) of fluvastatin, for example, administered once a day.
  • preferred dosage unit forms of ACE inhibitors are, for example, tablets or capsules comprising e.g. from about 5 mg to about 20 mg, preferably 5 mg, 10 mg, 20 mg or 40 mg, of benazepril; from about 6.5 mg to 100 mg, preferably 6.25 mg, 12.5 mg, 25 mg, 50 mg, 75 mg or 100 mg, of captopril; from about 2.5 mg to about 20 mg, preferably 2.5 mg, 5 mg, 10 mg or 20 mg, of enalapril; from about 10 mg to about 20 mg, preferably 10 mg or 20 mg, of fosinopril; from about 2.5 mg to about 4 mg, preferably 2 mg or 4 mg, of perindopril; from about 5 mg to about 20 mg, preferably 5 mg, 10 mg or 20 mg, of quinapril, or from about 1.25 mg to about 5 mg, preferably 1.25 mg, 2.5 mg, or 5 mg, of ramipril. Preferred is t.i.d. administration.
  • the film-coated tablet is manufactured e.g. as follows:
  • a mixture of valsartan, microcrystalline cellulose, crospovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200, silicon dioxide and magnesium stearate is premixed in a diffusion mixer and then sieve through a screnning mill.
  • the resulting mixture is again pre-mixed in a diffusion mixer, compacted in a roller compacter and then sieve through a screening mill,
  • the rest of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosile 200 are added and the final blend is made in a diffusion mixer.
  • the whole mixture is compressed in a rotary tabletting machine and the tabletts are coated with a film by using Diolack pale red in a perforated pan.
  • the film-coated tablet is manufactured e.g. as described in Formulation Example 1.
  • Valsartan and microcrystallin cellulose are spray-granulated in a fluidised bed granulator with a granulating solution consisting of povidone and sodium lauryl sulphate dissolved in purified water.
  • the granulate obtained is dried in a fluidiesd bed dryer.
  • the dried granulate is milled together with crospovidone and magnesium stearate.
  • the mass is then blended in a conical srew type mixer for approximately 10 minutes.
  • Teh empty hard gelatin capsules are filled with the blended bulk granules under controlled temperature and humidity conditions.
  • the filed capsules are dedustee, visually inspected, weightchecked and quarantied until by Quality assurance department.
  • Components Composition Per Unit (mg) Valsartan [ active ingredient] 160.00 Microcrystalline cellulose 50.20 Crospovidone 26.00 Povidone 25.00 Magnesium stearate 2.60 Sodium lauryl sulphate 1.20 Shell Iron oxide, red 0.123 (C.I. No. 77491, EC No. E 172) Iron oxide, yellow 0.123 (C.l. No. 77492, EC No. E 172) Iron oxide, black 0.245 (C.l. No. 77499, EC No. E 172) Titanium dioxide 1.540 Gelatin 74.969 Total tablet mass 342.00 The formulation is manufactured e.g. as described in Formulation Example 4.
  • Example 7 8 9 10 11 Components Amount per Unit (mg) Amount per Unit (mg) Amount per Unit (mg) Amount per Unit (mg) Amount per Unit (mg) Granulation Valsartan Drug Substance 80.000 160.000 40.000 320.000 320.000 Microcrystalline Cellulose (NF, Ph.Eur.)/ Avicel PH 102 54.000 108.000 27.000 216.000 216.000 Crospovidone (NF, Ph-Eur.) 15.000 30.000 7.500 80.000 60.000 60.000 Colloidal Anhydrous Silica (Ph.
  • NF 3.00 3.00 3.00 3.00 Microcrystalline Cellulose NF 18.00 18.00 18.00 24.25 Hydrogenated Castor Oil, NF 8.00 8.00 Magnesium Stearate, NF 8.00 1.75 Color: 0.50 Yellow-Brown (suspension) 2.00 Red-Brown (suspension) 0.50 Purified Water, USP trace trace trace trace trace Opadry Color: Yellow 8.38 8.38 Pink 8.38 8.38 Total 193.38 190.38 183.88 183.88
  • hemi-fumarate of the compound of formula (I) 1000 g corn starch 680 g colloidal silicic acid 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water quantum satis
  • a mixture of one of the compounds of formula I mentioned in the preceding Examples as active ingredient 50 g of corn starch and the colloidal silicic acid is processed into a moist mass with starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water. The mass is forced through a sieve having a mesh size of 3 mm and dried at 45° for 30 minutes in a fluidised bed drier. The dried granules are pressed through a sieve having a mesh size of 1 mm, mixed with a previously sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch, and compressed to form slightly biconvex tablets.
EP10179109.3A 2000-11-17 2001-11-15 Mélange synergétique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires Expired - Lifetime EP2305232B1 (fr)

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GB0028151A GB0028151D0 (en) 2000-11-17 2000-11-17 Combination of organic compounds
EP20010996377 EP1341533B1 (fr) 2000-11-17 2001-11-15 Complexes medicamenteux comportant un inhibiteur de la renine et servant au traitement de maladies cardiovasculaires
EP20080002401 EP1915993B1 (fr) 2000-11-17 2001-11-15 Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP20050015603 EP1602370B1 (fr) 2000-11-17 2001-11-15 Mélange synergétique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
PCT/EP2001/013241 WO2002040007A1 (fr) 2000-11-17 2001-11-15 Complexes medicamenteux comportant un inhibiteur de la renine et servant au traitement de maladies cardiovasculaires

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EP08002401 Previously-Filed-Application 2001-11-15
EP20010996377 Division EP1341533B1 (fr) 2000-11-17 2001-11-15 Complexes medicamenteux comportant un inhibiteur de la renine et servant au traitement de maladies cardiovasculaires
EP20080002401 Previously-Filed-Application EP1915993B1 (fr) 2000-11-17 2001-11-15 Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP20080002401 Division EP1915993B1 (fr) 2000-11-17 2001-11-15 Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP01996377.6 Division 2001-11-15
EP05015603.3 Division 2005-07-19
EP08002401.1 Division 2008-02-08

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EP20100179116 Withdrawn EP2305233A1 (fr) 2000-11-17 2001-11-15 Mélange synergétique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP10179109.3A Expired - Lifetime EP2305232B1 (fr) 2000-11-17 2001-11-15 Mélange synergétique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP20080002604 Withdrawn EP1930000A1 (fr) 2000-11-17 2001-11-15 Combinaison de composés organiques
EP20100179101 Withdrawn EP2305231A1 (fr) 2000-11-17 2001-11-15 Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP20080002401 Revoked EP1915993B1 (fr) 2000-11-17 2001-11-15 Mélange synergique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires
EP20050015603 Revoked EP1602370B1 (fr) 2000-11-17 2001-11-15 Mélange synergétique comprenant un inhibiteur de la rénine pour le traitement des maladies cardiovasculaires

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Families Citing this family (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1448190A2 (fr) * 2001-10-18 2004-08-25 Novartis AG Sels comprenant un at1-recepteur antagoniste et un agent cardio-vasculaire
RU2316318C2 (ru) 2002-05-17 2008-02-10 Новартис Аг Фармацевтическая композиция, включающая ингибитор ренина, блокатор кальциевых каналов и диуретик
GB0212410D0 (en) 2002-05-29 2002-07-10 Novartis Ag Organic compounds
US20060013852A1 (en) * 2002-06-28 2006-01-19 Prescott Margaret F Use of organic compounds
JP4519640B2 (ja) * 2002-06-28 2010-08-04 シュペーデル・ファルマ・アーゲー 非ペプチドレニン阻害薬及び界面活性剤を含有する医薬製剤
SE0300988D0 (sv) * 2003-04-03 2003-04-03 Astrazeneca Ab New use
TW200513461A (en) 2003-10-01 2005-04-16 Speedel Experimenta Ag Organische verbindungen
GB0325605D0 (en) * 2003-11-03 2003-12-10 Novartis Ag Combination of organic compounds
US7582782B2 (en) * 2003-11-26 2009-09-01 Novartis Ag Organic compounds
GB0327839D0 (en) * 2003-12-01 2003-12-31 Novartis Ag Organic compounds
JP2007518777A (ja) * 2004-01-23 2007-07-12 シュペーデル・エクスペリメンタ・アーゲー アミノアルコール誘導体およびレニン阻害剤としてのその使用
WO2005070871A2 (fr) * 2004-01-23 2005-08-04 Speedel Experimenta Ag Composes organiques
DE602005022060D1 (de) * 2004-01-23 2010-08-12 Novartis Ag Diaminoalkohole und deren verwendung als renininhibitoren
PE20110121A1 (es) 2004-03-17 2011-02-28 Novartis Ag Composiciones farmaceuticas de aliskiren
US20080161321A1 (en) * 2004-03-17 2008-07-03 David Louis Feldman Use of Renin Inhibitors in Therapy
TW200609215A (en) * 2004-03-19 2006-03-16 Speedel Experimenta Ag Organic compounds
WO2005099695A1 (fr) * 2004-04-19 2005-10-27 Novartis Ag Systemes d'administration de medicament destine a la prevention et au traitement de maladies vasculaires
KR20130048281A (ko) * 2004-10-08 2013-05-09 노파르티스 아게 확장기 기능장애 또는 확장기 심부전의 예방 또는 치료를 위한 레닌 억제제의 용도
GB0428250D0 (en) * 2004-12-23 2005-01-26 Novartis Ag Organic compounds
MY146830A (en) * 2005-02-11 2012-09-28 Novartis Ag Combination of organic compounds
TW200722424A (en) 2005-03-31 2007-06-16 Speedel Experimenta Ag Substituted piperidines
EP1897879A3 (fr) 2005-03-31 2008-06-11 Speedel Experimenta AG Pipéridines 2,4,5-substituées comme inhibiteurs de la rénine
BRPI0609915A2 (pt) * 2005-04-27 2010-05-25 Novartis Ag métodos para tratar aterosclerose
GB0511686D0 (en) * 2005-06-08 2005-07-13 Novartis Ag Organic compounds
CN1732952B (zh) * 2005-09-02 2010-04-07 姚俊华 一种治疗高血压的复方分散片
US8158146B2 (en) 2005-09-28 2012-04-17 Teva Pharmaceutical Industries Ltd. Stable combinations of amlodipine besylate and benazepril hydrochloride
EP1932528A1 (fr) * 2005-09-28 2008-06-18 Teva Pharmaceutical Industries Ltd Composition stable de basylate d'amlodipine
JP2009514961A (ja) * 2005-11-08 2009-04-09 ノバルティス アクチエンゲゼルシャフト アンギオテンシンｉｉ受容体ブロッカー、カルシウムチャネルブロッカーおよび他の活性剤の組合せ
AR057882A1 (es) 2005-11-09 2007-12-26 Novartis Ag Compuestos de accion doble de bloqueadores del receptor de angiotensina e inhibidores de endopeptidasa neutra
WO2007106494A2 (fr) * 2006-03-13 2007-09-20 Encysive Pharmaceuticals, Inc. Procedes et compositions pour le traitement d'une insuffisance cardiaque diastolique
US20070260203A1 (en) * 2006-05-04 2007-11-08 Allergan, Inc. Vasoactive agent intraocular implant
GB0612540D0 (en) 2006-06-23 2006-08-02 Novartis Ag Galenical formulations of organic compounds
TW200831463A (en) * 2006-09-12 2008-08-01 Speedel Experimenta Ag Nitrate esters of aminoalcohols
KR100888131B1 (ko) * 2006-10-10 2009-03-11 한올제약주식회사 시간차 투약 원리를 이용한 심혈관계 질환 치료용 복합제제
RU2009126741A (ru) * 2006-12-15 2011-01-20 Новартис АГ (CH) Ингибиторы ренина, предназначенные для профилактики и лечения гипертензии у пациентов, страдающих от ожирения
EP2120899A1 (fr) * 2007-02-14 2009-11-25 Gilead Colorado, Inc. Combinaison de médicaments antihypertenseurs
MX2010003441A (es) * 2007-09-28 2010-04-21 Novartis Ag Formulaciones galenicas de alisquireno y valsartan.
EP2062874B1 (fr) 2007-11-20 2014-12-17 KRKA, tovarna zdravil, d.d., Novo mesto Procédé et intermédiaires pour la préparation d'aliskiren
KR101164300B1 (ko) 2008-02-22 2012-07-09 한올바이오파마주식회사 약제학적 제제
US20110111022A1 (en) 2008-04-10 2011-05-12 Hanall Biopharma Co., Ltd. Pharmaceutical formulation
WO2009127251A1 (fr) * 2008-04-16 2009-10-22 Novartis Ag Combinaisons renfermant un inhibiteur de la rénine
US20110117194A1 (en) 2008-04-29 2011-05-19 Hanall Biopharma Co., Ltd. Pharmaceutical formulation containing angiotensin-ii receptor blocker
WO2010024772A1 (fr) * 2008-08-29 2010-03-04 Medivir Ab Inhibiteurs d'aspartyl protéases
EP2189442B1 (fr) 2008-11-20 2014-10-01 Krka Tovarna Zdravil, D.D., Novo Mesto Procédé et intermédiaires pour la préparation d'aliskiren
US20120009257A1 (en) 2009-03-20 2012-01-12 Indrajit Ghosh Galenical Formulations of a Fixed Dose Combination of Valsartan and Aliskiren
CN101926793B (zh) * 2010-08-05 2012-08-15 成都自豪药业有限公司 一种含替米沙坦和阿利吉伦的联合用药物及其制备方法
WO2012152718A1 (fr) 2011-05-06 2012-11-15 Farmicom Pharmaceutical Company D.O.O. Composition comprenant un antagoniste de récepteur d'angiotensine ii et un antioxydant pour maintenir et/ou améliorer les propriétés de la peau
RU2483750C1 (ru) * 2012-03-19 2013-06-10 Общество с ограниченной ответственностью "СупраГен" Способ лечения больных с острым инфарктом миокарда с подъемом сегмента st
JP2015516441A (ja) * 2012-05-18 2015-06-11 ルオダ ファーマ ピーティーワイ リミテッド 液体配合剤
RU2554815C1 (ru) * 2014-06-18 2015-06-27 Общество с ограниченной ответственностью "Нанолек" Гипотензивное средство
EP3174530B1 (fr) 2014-07-30 2018-08-29 Merck Patent GmbH Polyalcools de vinyle aptes à la compression directe

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017771A1 (fr) * 1990-05-11 1991-11-28 Pfizer Inc. Compositions et procedes therapeutiques synergiques
WO1992010097A1 (fr) * 1990-12-14 1992-06-25 Smithkline Beecham Corporation Compositions de blocage de recepteur de l'angiotensine ii
US5559111A (en) * 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides

Family Cites Families (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4617307A (en) 1984-06-20 1986-10-14 Ciba-Geigy Corporation Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors
US4889861A (en) 1982-12-21 1989-12-26 Ciba-Geigy Corp. Substituted imidazo[1,5-a]pyridine derivatives and other substituted bicyclic derivatives and their use as aromatase inhibitors
FI77669C (fi) 1983-04-13 1989-04-10 Ciba Geigy Ag 20-spiroxaner och analoger, som innehaoller en oeppen ring e, foerfarande foer deras framstaellning samt dessa innehaollande farmaceutiska preparat.
US4782043A (en) 1983-06-15 1988-11-01 Merck & Co., Inc. Renin inhibitors containing a C-terminal amide cycle
US4898729A (en) 1983-12-09 1990-02-06 Euroceltique, S.A. Treatment of hypertension, compounds and compositions for antihypertension and diuresis
US4812442A (en) 1984-05-29 1989-03-14 Merck & Co., Inc. Tripeptide renin inhibitors
CA1334092C (fr) 1986-07-11 1995-01-24 David John Carini Imidazoles bloquant les recepteurs de l'angiotensine ii
US5594021A (en) 1993-05-20 1997-01-14 Texas Biotechnology Corporation Thienyl-, furyl- and pyrrolyl sulfonamides and derivatives thereof that modulate the activity of endothelin
US4927807A (en) 1987-10-06 1990-05-22 Abbott Laboratories Glaucoma treatment
SE8802428D0 (sv) * 1988-06-28 1988-06-28 Haessle Ab New compounds
US5268374A (en) 1988-10-04 1993-12-07 Abbott Laboratories Non-peptide renin inhibitors
US5164388A (en) 1988-10-19 1992-11-17 Abbott Laboratories Heterocyclic peptide renin inhibitors
DE69034103T2 (de) 1989-06-14 2004-07-15 Smithkline Beecham Corp. Imidazoalkensäure
EP0438311A3 (en) * 1990-01-19 1992-07-01 Merck & Co. Inc. Di- and tripeptide renin inhibitors
US5182266A (en) * 1990-01-31 1993-01-26 Abbott Laboratories Method for treating renal disease
PH30484A (en) 1990-02-19 1997-05-28 Ciba Geigy Acy compounds pharmaceutical composition containing said compound and method of use thereof
NZ237476A (en) 1990-03-20 1994-01-26 Sanofi Sa N-substituted heterocyclic compounds and pharmaceutical compositions.
US5196444A (en) 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
US5821232A (en) 1990-05-11 1998-10-13 Pfizer Inc. Synergistic therapeutic compositions and methods
IE68045B1 (en) 1990-05-11 1996-05-15 Abbott Lab Renin inhibitors
WO1992000972A1 (fr) 1990-07-11 1992-01-23 Abbott Laboratories Composes inhibiteurs de renine
JPH06500111A (ja) * 1990-08-15 1994-01-06 アボツト・ラボラトリーズ レニン阻害剤
US5656650A (en) * 1990-12-14 1997-08-12 Smithkline Beecham Corp. Angiotensin II receptor blocking compositions
EP0498361A3 (en) 1991-02-06 1992-09-02 Schering Corporation Combination of an angiotensin ii antagonist or renin inhibitor with a neutral endopeptidase inhibitor
CA2229000C (fr) 1991-02-21 2002-04-09 Sankyo Company, Limited Derives de 1-biphenylimidazole, leur preparation et leur utilisation therapeutique
RU2086544C1 (ru) * 1991-06-13 1997-08-10 Хоффманн-Ля Рош АГ Бензолсульфонамидные производные пиримидина или их соли, фармацевтическая композиция для лечения заболеваний, связанных с активностью эндотелина
DE4121975A1 (de) 1991-07-03 1993-01-07 Basf Ag Thermoplastische formmassen auf der basis von polycarbonaten, styrol/acrylnitril-polymerisaten und polyolefinen
US5256667A (en) * 1991-09-25 1993-10-26 Merck & Co., Inc. Quinazolinones and pyridopyrimidinones
TW226375B (fr) 1991-10-24 1994-07-11 American Home Prod
US6057344A (en) 1991-11-26 2000-05-02 Sepracor, Inc. Methods for treating hypertension, and angina using optically pure (-) amlodipine
KR100331667B1 (ko) 1993-04-27 2002-11-08 스미스클라인 비참 코포레이션 엔도텔린수용체길항제
US5508272A (en) 1993-06-15 1996-04-16 Bristol-Myers Squibb Company Compounds containing a fused bicycle ring and processes therefor
DK0634175T3 (da) * 1993-07-15 2001-04-30 Hoffmann La Roche Farmaceutisk kombination, der indeholder en hæmmer af renin-angiotensin-systemet og en endothelin-antagonist
PT714897E (pt) 1993-08-18 2001-05-31 Banyu Pharma Co Ltd Derivado ciclopenteno heteroaromatico fundido possuindo actividade de antagonista de endotelinas
US5606078A (en) 1994-04-18 1997-02-25 Ciba-Geigy Corporation 3,5-Disubstituted tetrahydrofuran-2-ones
US5659065A (en) 1994-04-18 1997-08-19 Novartis Corporation Alpha-aminoalkanoic acids and reduction products
US5562921A (en) 1994-07-15 1996-10-08 Sherman; Bernard C. Stable solid pharmaceutical compositions containing enalapril maleate
WO1996006095A1 (fr) 1994-08-19 1996-02-29 Abbott Laboratories Antagonistes d'endotheline
US5612359A (en) 1994-08-26 1997-03-18 Bristol-Myers Squibb Company Substituted biphenyl isoxazole sulfonamides
DE19533023B4 (de) 1994-10-14 2007-05-16 Basf Ag Neue Carbonsäurederivate, ihre Herstellung und Verwendung
TW313568B (fr) 1994-12-20 1997-08-21 Hoffmann La Roche
KR19980701690A (ko) 1995-01-27 1998-06-25 리 카핀 엔도텔린 길항제로서의 치환 페닐 화합물
US5846990A (en) 1995-07-24 1998-12-08 Bristol-Myers Squibb Co. Substituted biphenyl isoxazole sulfonamides
JPH0971586A (ja) * 1995-09-07 1997-03-18 Yamanouchi Pharmaceut Co Ltd 新規な二環性縮合イミダゾール誘導体
US5696166A (en) 1995-10-31 1997-12-09 Yanni; John M. Compositions containing hydroxyeicosatetraenoic acid derivatives and methods of use in treating dry eye disorders
AU703386B2 (en) 1995-12-20 1999-03-25 Astellas Pharma Inc. Arylethenesulfonamide derivatives and drug composition containing the same
IT1277737B1 (it) 1995-12-28 1997-11-12 Zambon Spa Derivati tiolici ad attivita' inibitrice delle metallopeptidasi
AU1319697A (en) 1996-01-23 1997-08-20 Shionogi & Co., Ltd. Process for producing oleanolic acid analogs by culturing hairy root
BR9708525A (pt) 1996-04-04 1999-08-03 Banyu Pharma Co Ltd Método de tratamento de insuficência cardíaca com antagonistas de endotelina
GB9613470D0 (en) 1996-06-27 1996-08-28 Ciba Geigy Ag Small solid oral dosage form
GT199800126A (es) * 1997-08-29 2000-01-29 Terapia de combinacion.
WO1999065500A1 (fr) * 1998-06-17 1999-12-23 Bristol-Myers Squibb Company Prevention de l'infarctus cerebral par administration d'une combinaison d'un anti-agregant plaquettaire bloquant les recepteurs d'adp et d'un medicament antihypertenseur
IL140905A0 (en) 1998-07-20 2002-02-10 Smithkline Beecham Corp Bioenhanced formulations comprising eprosartan in oral solid dosage form
UA74141C2 (uk) * 1998-12-09 2005-11-15 Дж.Д. Сірл Енд Ко. Фармацевтична композиція на основі тонкоподрібненого еплеренону (варіанти), спосіб її одержання та спосіб лікування розладів, опосередкованих альдостероном (варіанти)
WO2000056403A1 (fr) * 1999-03-19 2000-09-28 The Brigham And Women's Hospital, Inc. Regulation positive de l'oxyde nitrique synthase des cellules endotheliales de type iii par des inhibiteurs de la hmg-coa reductase
DE60036122T2 (de) 1999-11-09 2008-05-15 Pharmacia Corp. Verwendung von eplerenon zur behandlung von restenose
US20030114389A1 (en) * 2001-11-13 2003-06-19 Webb Randy Lee Combination of organic compounds
RU2316318C2 (ru) * 2002-05-17 2008-02-10 Новартис Аг Фармацевтическая композиция, включающая ингибитор ренина, блокатор кальциевых каналов и диуретик
EP1581729B1 (fr) 2002-12-31 2008-05-28 Volkswagen Aktiengesellschaft Procede de commande d'un moteur a combustion interne et moteur a combustion interne apte a fonctionner avec un melange pauvre

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017771A1 (fr) * 1990-05-11 1991-11-28 Pfizer Inc. Compositions et procedes therapeutiques synergiques
WO1992010097A1 (fr) * 1990-12-14 1992-06-25 Smithkline Beecham Corporation Compositions de blocage de recepteur de l'angiotensine ii
US5559111A (en) * 1994-04-18 1996-09-24 Ciba-Geigy Corporation δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MUTSCHLER E., SCHÄFER-KORTING M.: "Arzneimittelwirkungen Lehrbuch der Pharmakologie und Toxikologie", 1996, WISSENSCHAFTLICHE VERLAGSGESELLSCHAFT, Stuttgart, pages: 481 - 492, XP002620274 *
RAHUEL J ET AL: "Structure-based drug design: The discovery of novel nonpeptide orally active inhibitors of human renin", CHEMISTRY AND BIOLOGY (LONDON), vol. 7, no. 7, July 2000 (2000-07-01), pages 493 - 504, XP002620273, ISSN: 1074-5521 *

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